Idiopathic or primary diabetes mellitus is a chronic disorder of carbohydrate, fat, and protein metabolism characterized in its fully expressed form by an absolute or relative insulin deficiency, fasting hyperglycemia, glycosuria, and a striking tendency toward development of atherosclerosis, microangiopathy, nephropathy, and neuropathy. Underutilization of glucose is characteristic of all diabetic patients, but only some have a clearly defined severe insulin deficiency resulting from a loss of p cells. The large remainder of diabetic patients suffer from some impairment of insulin secretory response associated with a marked resistance to insulin in the peripheral tissues.
The phrase "idiopathic diabetes mellitus" embraces a heterogeneous group of disorders having in common the above-described characteristics. At least two major as well as several less common variants of the disease have been identified. One major variant, insulin-dependent diabetes mellitus (IDDM) (Type 1), accounts for about 10% of diabetics. A second major variant, non-insulin-dependent diabetes mellitus (NIDDM) (Type II) represents the remaining 90% of all diabetic patients. Robbins, S. L. et al. Pathologic Basis of Disease, 3rd Edition (W. B. Saunders Company, Philadelphia, 1984) p. 972. Absent regular insulin replacement therapy using exogenously produced insulin and/or careful monitoring of the diet of diabetic patients, such patients experience a wide range of debilitating symptoms, some of which can progress into coma and ultimately death.
An alternative method of treating diabetes presently under investigation, which does not require repeated administration of insulin and/or strict monitoring of diet, is transplantation of pancreatic cells or tissue from a donor to the diabetic patient. A major problem in pancreatic cell or tissue transplantation from one human to another for treatment of diabetes, however, is a shortage of donor tissue. Thompson, S. C. et al. (1990) Transplantation 49(3):571-581. Moreover, human pancreas will inevitably remain in limited supply and be subject to many constraints, including, especially with human fetal pancreatic cells or tissue, sensitive ethical issues. The improvement in patients and graft survival following human pancreas transplants (Sutherland, D. E. R. et al. (1987) Transplant. Proc. 19:113) will also mean that adult cadaveric pancreas may be more difficult to obtain for experimental purposes.
As a result of the above-described problems associated with transplantation of pancreatic tissue from a human donor to a human recipient, alternative sources of pancreatic tissue for transplantation have been investigated. Several groups of investigators have conducted research involving the use of pancreatic cells and tissue from animal sources, such as swine, for transplantation. See e.g., Korsgren, O. et al. (1993) Surgery 113:205-214; Braesch, M. K. et al. (1992) Transplant. Proc. 24(2):679-680; Groth, C. G. et al. (1992) Transplant. Proc. 24(3):972-973; Liu, X. et al. (1991) Diabetes 40:858-866; Korsgren, O. et al. (1991) Diabetologia 34:379-386; Yoneda, K. et al. (1989) Diabetes 38 (Supp. 1):213-216; Wilson, J. D. et al. (1989) Diabetes 38 (Suppl. 1):217-219; Korsgren, O. et al. (1989) Diabetes 38 (Suppl. 1):209-212; Korsgren, O. et al. (1988) Transplantation 45(3):509-514; Sasaki, N. et al. (1984) Transplantation 38(4):335-340. Several of these investigators report transplantation of pancreatic tissue samples containing insulin-secreting and at least partially differentiated porcine pancreatic cells into xenogeneic subjects after short-term culture. However, these short-term cultures of pancreatic cells often display eventual necrosis (Thompson, S. C. et al. (1990) Transplantation 49(3):571-581), developmental stagnation (Liu, X. et al. (1991) Diabetes 40:858-866; Korsgren, O. et al. (1989) Diabetes 38 (Suppl. 1):209-212; Korsgren, O. et al. (1988) Transplantation 45(3):509-514), decreased proliferation (Liu, X. et al. (1991) Diabetes 40:858-866; Korsgren, O. et al. (1988) Transplantation 45(3):509-514), and decreased insulin production (Yoneda, K. et al. (1989) Diabetes 38 (Supp. 1):213-216; Korsgren, O. et al. (1988) Transplantation 45(3):509-514).